ReviewCell Biology

Retrograde signaling from autophagy modulates stress responses

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Sci. Signal.  28 Feb 2017:
Vol. 10, Issue 468, eaag2791
DOI: 10.1126/scisignal.aag2791

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Gloss

Macroautophagy is an important degradative process in the cell, responsible for recycling proteins and even whole organelles, such as mitochondria, when they become dysfunctional. A set of more than 30 autophagy-related (ATG) proteins carry out the functions of macroautophagy, mainly under the control of a master regulator, a protein kinase–containing complex called the mechanistic target of rapamycin complex 1 (mTORC1). However, ATG proteins can themselves play roles in numerous regulatory pathways, influencing the transcription factors that promote responses to stresses, such as nutrient or oxygen starvation, or DNA damage caused by irradiation or drugs. These ATG functions, which act in a retrograde fashion or upstream in the pathways responding to stresses, are the subject of this Review, which contains 7 figures, 1 table, and 112 citations.

Abstract

Macroautophagy is a process in which cytoplasmic components, including whole organelles, are degraded within lysosomes. Basally, this process is essential for homeostasis and is constitutively functional in most cells, but it can also be implemented as part of stress responses. We discuss findings showing that autophagy proteins can modulate and amplify the activities of transcription factors involved in stress responses, such as those in the p53, FOXO, MiT/TFE, Nrf2, and NFκB/Rel families. Thus, transcription factors not only amplify stress responses and autophagy but are also subject to retrograde regulation by autophagy-related proteins. Physical interactions with autophagy-related proteins, competition for activating intermediates, and “signalphagy,” which is the role autophagy plays in the degradation of specific signaling proteins, together provide powerful tools for implementing negative feedback or positive feed-forward loops on the transcription factors that regulate autophagy. We present examples illustrating how this network interacts to regulate metabolic and physiologic responses.

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